Copyright © 2006, European Society of Cardiology
Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts
aDepartment of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
bInserm U689, Centre de Cardiologie vasculaire de Lariboisiere, Paris, France
cDepartment of Biology, Portland State University, Portland, Oregon, United States
dInserm U.441, Avenue du Haut Leveque, Pessac, France
* Corresponding author. Tel.: +1 419 383 4182; fax: +1 419 383 2871. Email address: zxie{at}meduohio.edu
Objective: Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia–reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex.
Methods and results: In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 µM followed by an 8-minute washout before 30 min of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase C
1/protein kinase C
(PLC-1/PKC) pathway. Pre-treatment of the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) blocked not only ouabain-induced activation of PLC-1/PKC pathway, but also cardiac protection. This protection was also blocked by a PKC translocation inhibitor peptide (PKC TIP).
Conclusion: Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-1 and PKC.
KEYWORDS Ischemia; Reperfusion; Signal transduction; Na/K-pump
Time for primary review 15 days
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